Method for the preparation of therapeutically valuable triphenylbutene derivatives

ABSTRACT

The present invention concerns a method for the preparation of therapeutically valuable triphenylbutene derivatives, especially ospemifene or fispemifene.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Provisional PatentApplication Number 60/889,838 filed Feb. 14, 2007, hereby incorporatedby reference.

BACKGROUND

1. Field of the Invention

This invention relates to the preparation of two triphenylbutenederivatives, valuable in therapy as selective estrogen receptormodulators.

2. Description of Related Art

The publications and other materials used herein to illuminate thebackground of the invention, and in particular, cases to provideadditional details respecting the practice, are incorporated byreference.

“SERMs” (selective estrogen receptor modulators) have both estrogen-likeand antiestrogenic properties (Kauffman & Bryant, Drug News Perspect.8:531-539,1995). The effects may be tissue-specific as in the case oftamoxifen and toremifene which have estrogen-like effects in the bone,partial estrogen-like effect in the uterus and liver, and pureantiestrogenic effect in breast tissue. Based on the publishedinformation, many SERMs are more likely to cause menopausal symptomsthan to prevent them. They have, however, other important benefits inelderly women: they decrease total and LDL cholesterol, thus minimizingthe risk of cardiovascular diseases, and they may prevent osteoporosisand inhibit breast cancer growth in postmenopausal women.

Ospemifene, (Z)-2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol,which is one of the main metabolites of toremifene, is known as anestrogen agonist and antagonist (Kangas, Cancer Chemother. Pharmacol.(1990) 27:8-12; WO 96/07402 and WO 97/32574). Ospemifene has relativelyweak estrogenic and antiestrogenic effects in the classical hormonaltests (Kangas, 1990). It has anti-osteoporosis actions and it decreasestotal and LDL cholesterol levels in both experimental models and inhuman volunteers. It also has antitumor activity in an early stage ofbreast cancer development in an animal breast cancer model. Ospemifeneis also the first SERM which has been shown to have beneficial effectsin climacteric syndromes in healthy women. The use of ospemifene for thetreatment of certain climacteric disorders and atrophy-related diseasesor disorders in postmenopausal women is disclosed in WO 02/07718 and WO03/103649.

WO 01/36360 describes a group of SERMs, which are tissue-specificestrogens and which can be used in women in the treatment of climactericsymptoms, osteoporosis, Alzheimer's disease and/or cardiovasculardiseases without the carcinogenic risk. Certain compounds can be givento men to protect them against osteoporosis, cardiovascular diseases andAlzheimer's disease without estrogenic adverse events (gynecomastia,decreased libido etc.). Of the compounds described in said patentpublication, the compound(Z)-2-{2-[4-(4-chloro-1,2-diphenylbut-1-enyl)phenoxy]-ethoxy}ethanol(also known under the generic name fispemifene) has shown a veryinteresting hormonal profile suggesting that it will be especiallyvaluable for treating disorders in men. WO 2004/108645 and WO2006/024689 suggest the use of fispemifene for treatment or preventionof age-related symptoms in men, such as lower urinary tract symptoms anddiseases or disorders related to androgen deficiency in men.

Known methods for the syntheses of compounds like ospemifene andfispemifene include rather many steps. WO 02/090305 describes a methodfor the preparation of fispemifene, where in a first step atriphenylbutane compound with a dihydroxy substituted butane chain isobtained. This compound is in a second step converted to atriphenylbutene where the chain is 4-chlorosubstituted. Then the desiredZ-isomer is crystallized. Finally, the protecting group is removed torelease the ethanol-ethoxy chain of the molecule.

In the known methods, the separation of the desired Z isomer is tedious.The protection group used to protect the ethanol-ethoxy chain during thereaction steps, benzyl, is rather difficult to remove.

SUMMARY

Both ospemifene and fispemifene are likely to be commercialized in thenear future. Thus, there is a great need for powerful methods for thepreparation of these compounds in large scale.

Another object is to provide methods having common features so that thesyntheses of the compounds easily can be run by using the same kind ofequipment and materials.

Thus, according to one aspect, this invention concerns a method for thepreparation of a compound of formula (Ia) or (Ib):

wherein a compound of formula (II)

a) is alkylated with an alkylating reagent of the formulaX—(CH₂)₂—O—(CH₂)₂—O-Pr,

where X is Cl, Br, I, mesyloxy or tosyloxy, and Pr is a protectinggroup, to give a compound of formula (III)

which is subjected to removal of the protecting group Pr to give thecompound of formula (Ia), or

b) is alkylated with an alkylating reagent of the formula X—(CH₂)₂—O-Pr,where X is Cl, Br, I, mesyloxy or tosyloxy, and Pr is a protectinggroup, to give a compound of formula (IV)

which is subjected to removal of the protecting group Pr to give thecompound of formula (Ib), or

c) is alkylated with an alkylating reagent of the formula X—CH₂—COOR,wherein X is Cl, Br, I, mesyloxy or tosyloxy, and R is an alkyl, to givea compound of formula (V)

and the ester is reduced to give the compound of formula (Ib).

DETAILED DESCRIPTION

Fispemifene is the Z-isomer of the compound of formula (Ia)

and ospemifene is the Z-isomer of the compound of formula (Ib)

The common starting material in the syntheses of (Ia) or (Ib), namelycompound (II), is previously known (Toivola, 1990; EP 0095875).According to a method disclosed in EP 095875, this compound was preparedby dealkylation of a corresponding ether to give (II). The method may beused to produce a mixture of isomers of compounds (Ia) and (Ib), butmost preferably is used to prepare the pure E- and Z-isomers of thosecompounds.

Particularly in case Z-isomers of the compounds (Ia) or (Ib) aredesired, a preferable method for the synthesis of compound (II) is aMcMurry reaction of commercially available starting materials,4-hydroxybenzophenone with 3-chloropropiophenone. The McMurry reactionis a well-known reductive coupling of ketones involving two steps: (1) asingle electron transfer to the carbonyl groups from an alkali metal,followed by (2) deoxygenation of the 1,2-diol with low-valent titaniumto yield the alkene. This reaction produces mainly the Z-isomer ofcompound (II).

The alkylation in steps a) and b) is carried out in an organic solvent,preferably carried out in tetrahydrofuran. It is also preferable to adda base to the solvent, most preferably sodium hydride.

The step of alkylation is performed at a temperature and a time toachieve substantial alkylation of compound 11.

The protecting group Pr can be any suitable protecting group such asbenzyl, substituted benzyl, allyl, tetrahydropyranyl or any otheralcohol protecting group obvious to one skilled in the art; see forexample Protecting Groups in Organic Synthesis, Third Edition, T. W.Greene and P. G. M. Wuts. Wiley Interscience, 1999 pp 23-200. In apreferable embodiment the protecting group is tetrahydropyranyl. Thisprotecting group is very easily removable by methods known to those ofordinary skill in the art. For example, acid labile alcohol protectinggroups such as a tetrahydropyranyl group (e.g., 2-tetrahydropyranyl) canbe removed using acid such as HCl. A benzyl group can be removed usingmethods such as hydrogenation with Pd on carbon as a catalyst, orreacting with Zn powder and acetyl chloride.

X is preferably I or Br in the alkylating reagent in steps a) and b).

In the alkylating reagent in step c) X is preferably I, Br, or Cl, mostpreferably Br.

The alkyl substituent R in the alkylating reagent in step c) ispreferably a C₁₄-alkyl, most preferably ethyl.

The reduction of compound (V) obtained in step c) is carried out with areducing agent, preferably lithium aluminum hydride. Other reducingagents are well known to those of ordinary skill in the art. The stepsof the methods described herein are carried out at temperatures and fortimes sufficient to achieve the desired compounds (Ia) and (Ib). Theselection of the parameters based on the disclosure herein can readilybe made by one of ordinary skill without undue experimentation.

To sum up, the preferred embodiments according to the present inventionprovides considerable advantages over known methods for producingcompounds of formula (Ia) or (Ib):

-   -   The use of tetrahydrofuran as solvent and sodium hydride as a        base in the alkylating steps a) and b) gives the desired        products in good yields.    -   The use of tetrahydropyranyl as protecting group is favorable        because this protecting group is easy to remove leading to good        yield of the product.    -   The McMurry synthesis of compound (II) leads mainly to the        Z-isomer. This is of particular importance when Z-isomers of the        end products Ia and Ib are desired.

The invention will be illuminated by the following non-restrictiveExamples.

EXAMPLE 1 4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (Compound II)

Zinc (15.0 g, 0.23 mol) and tetrahydrofuran (THF) (180 ml) was added tothe reaction vessel and cooled to −10° C. Titan tetrachloride was addeddropwise to the mixture (21.6 g, 0.114 mol) at about −10° C. After theaddition was completed the mixture was refluxed for two hours. Then themixture was cooled to 40° C. and 4-hydroxybenzophenone (7.68 g, 0.039mol) and 3- chloropropiophenone (6.48 g, 0.039 mol) dissolved in THF (75ml) were added to the mixture. Refluxing was continued for additional3.5 hours. The cooled reaction mixture was poured in aqueous potassiumcarbonate solution (21 g K₂CO₃+210 ml water) and allowed to standovernight at the ambient temperature. The mixture was filtered and theprecipitate was washed with THF. The filtrate was evaporated to dryness.The residue was dissolved in ethyl acetate and washed with water. Ethylacetate phase was evaporated to dryness and the residue was crystallizedfirst from methanol-water (8:2) and then from methanol-water (9:1).Yield 5.4 g.

Z-isomer: ¹ H NMR (CDCl₃): 2.92 (t, 2H,=CH₂CH₂Cl), 3.42 (t,2H,=CH₂CH₂Cl), 6.48 (d, 2H, aromatic proton ortho to hydroxy), 6.75 (d,2H, aromatic proton meta to hydroxy), 7.1-7.4 (m, 10H, aromatic protons)

EXAMPLE 2 2-(2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]ethoxy}-ethoxy)-tetrahydropyran(Compound III, where Pr is tetrahydropyranyl)

4-(4-Chloro-1 ,2-diphenyl-but-1-enyl)phenol (0.33 g, 0.001 mol) wasdissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere. Sodiumhydride (0.036 g, 0.0015 mol) was added to the solution and the mixturewas stirred at room temperature for an hour.2-[2-(2-iodo-ethoxy)-ethoxy)-tetrahydropyran (0.6 g, 0.002 mol) wasadded and the mixture was refluxed for 3 hours. After cooling and addingwater the mixture was extracted three times with ethyl acetate. Theorganic phase was dried with sodium sulphate and evaporated to dryness.The residue was used in the next reaction step without furtherpurification.

EXAMPLE 3 2-{2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]ethoxy}-ethanol (Compound Ia)

The residue of the previous reaction step (Example 2) was dissolved inethanol (10 ml) and the solution was acidified with 2 N aqueous hydrogenchloride. The mixture was stirred over night at ambient temperature.Then the solvent was evaporated, water was added and the mixture wasextracted three times with dichloromethane. The organic phase was washedwith water, dried with sodium sulphate and evaporated to dryness. Theresidue was crystallized from heptane-ethyl acetate (8:2). Yield 0.216g.

Z-isomer, ¹H NMR (CDCl₃): 2.92 (t, 2H,=CH₂CH₂Cl), 3.42 (t,2H,=CH₂CH₂Cl), 3.58-3.65 (m, 2H, OCH₂CH₂OH), 3.7-3.82 (m,4H,−CH₂OCH₂CH₂O H), 3.97-4.04 (m, 2H, ArOCH²⁻), 6.56 (d, 2H, aromaticproton ortho to hydroxy), 6.78 (d, 2H, aromatic proton meta to hydroxy),7.1-7.43 (m, 10H, aromatic protons)

EXAMPLE 4 2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol(Compound Ib)

4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.23 g, 0.689 mmol) wasdissolved in tetrahydrofuran (3 ml) under nitrogen atmosphere. Sodiumhydride (0.025 g, 1.03 mmol) was added to the solution and the mixturewas stirred at room temperature for an hour.2-(2-iodo-ethoxy)-tetrahydropyran (0.3 g, 1.17 mmol) was added and themixture was refluxed for 2 hours. Additional portions of2-(2-iodo-ethoxy)-tetrahydro-pyran (0.5 g, 2 mmol) were added to themixture during seven hours. After cooling and adding water, THF wasevaporated and the mixture was extracted three times with ethyl acetate.The organic phase was washed with 2 N aqueous sodium hydroxide andwater, dried with sodium sulphate and evaporated to dryness. The residue(which is Compound (IV) where Pr is tetrahydropyranyl) was dissolved inethanol and acidified with 2 N aqueous hydrogen chloride solution. Themixture was stirred at room temperature over night, evaporated andextracted with dichloromethane. After washing with water the organicphase was dried (Na₂SO₄) and evaporated. The residue was purified byflash chromatography with dichloromethane/methanol 9.5/0.5 as eluent.Yield 0.17 g, 59%.

Z-isomer, ¹H NMR (CDCl₃): 2.92 (t, 2H, =CH₂CH₂Cl), 3.42 (t, 2H,=CH₂CH₂Cl), 3.85-3.89 (m, 4H, OCH₂CH₂), 6.56 (d, 2H, aromatic protonortho to hydroxy), 6.80 (d, 2H, aromatic proton meta to hydroxy),7.1-7.43 (m, 10H, aromatic protons).

EXAMPLE 5 2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol(Compound Ib)

The compound was prepared by the same method as described in Example 4using 2-(2-iodo-ethoxymethyl)-benzene as a reagent and removing thebenzylic protecting group using the method described in Example (e) ofU.S. Pat. No. 6,891,070 B2, herein incorporated by reference. Briefly,the removal is carried out under a nitrogen atmosphere, in the presenceof Zn powder and acetyl chloride.

EXAMPLE 6 [4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-acetic acidethyl ester (Compound V where R is ethyl)

4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.5 g, 0.0015 mol), absoluteethanol (10 ml), potassium carbonate (0.62 g, 0.0045 mol) and ethylbromo acetate (0.373 g, 0.00224 mol) are mixed under nitrogen atmosphereand refluxed for 2.5 hours. Then the hot mixture was filtered and theprecipitate was washed with absolute ethanol. The filtrate wasevaporated, extracted with ethyl acetate and washed with water. Ethylacetate was dried (Na₂SO₄) and evaporated to dryness. Yield 260 mg, 52%.The product was used without further purification in the next reactionstep.

¹H NMR (CDCl₃₊ MeOH-_(d4)): 1.25 (t, 3H, CH₂CH₃), 2.92 (t, 2H,=CH₂CH₂Cl), 3.42 (t, 2H, =CH₂CH₂Cl), 4.22 (q, 2H, OCH₂CH₃), 4.49 (s, 2H,ArOCH₂₋), 6.56 (d, 2H, aromatic proton ortho to hydroxy), 6.80 (d, 2H,aromatic proton meta to hydroxy), 7.1-7.43 (m, 10H, aromatic protons).

An alternative way to carry out the alkylation described in Example 6 isto replace absolute ethanol and potassium carbonate by sodium hydrideand tetrahydrofuran. Preliminary experiments gave the product in highyield (90%) after a short reaction time (about 1 hour) at roomtemperature.

EXAMPLE 7 2-[4-(4-Chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethanol(Compound Ib)

[4-(4-Chloro-1 ,2-diphenyl-but-1-enyl)-phenoxy]-acetic acid ethyl ester(Example 7) was dissolved in tetrahydrofuran at room temperature undernitrogen atmosphere. Lithium aluminium hydride was added to the solutionin small portions until the reaction was complete. The reaction wasquenched by adding saturated ammonium chloride solution to the mixture.The product was extracted into toluene, which was dried and evaporatedin vacuo. The yield 100 mg, 43%.

¹H NMR (CDCl₃): 2.92 (t, 2H, =CH₂CH₂Cl), 3.42 (t, 2H, =CH₂CH₂Cl),3.85-3.89 (m, 4H, OCH₂CH₂), 6.56 (d, 2H, aromatic proton ortho tohydroxy), 6.80 (d, 2H, aromatic proton meta to hydroxy), 7.1-7.43 (m,10H, aromatic protons).

It will be appreciated that the methods of the present invention can beincorporated in the form of a variety of embodiments, only a few ofwhich are disclosed herein. It will be apparent to one of ordinary skillin the art that other embodiments exist and do not depart from thespirit of the invention. Thus, the described embodiments areillustrative and should not be construed as restrictive.

1. A method for the preparation of a compound of formula (Ia) or (Ib)

wherein a compound of formula (II)

a) is alkylated with an alkylating reagent of the formulaX—(CH₂)₂—O—(CH₂)₂—O-Pr, where X is Cl, Br, 1, mesyloxy or tosyloxy, andPr is a protecting group, to give a compound of formula (III)

which is subjected to removal of the protecting group Pr to give thecompound of formula (Ia), or b) is alkylated with an alkylating reagentof the formula X—(CH₂)₂—O-Pr, where X is Cl, Br, I, mesyloxy ortosyloxy, and Pr is a protecting group, to give a compound of formula(IV)

which is subjected to removal of the protecting group Pr to give thecompound of formula (Ib), or c) is alkylated with an alkylating reagentof the formula X—CH₂—COOR, wherein X is Cl, Br, I, mesyloxy or tosyloxy,and R is an alkyl, to give a compound of formula (V)

and the ester is reduced to give the compound of formula (Ib).
 2. Themethod according to claim 1 or 2, wherein the compound of formula (II)is prepared by a McMurry reaction of 4-hydroxybenzophenone with3-chloropropiophenone.
 3. The method according to claim 1 or 2, whereinthe alkylation in step a) or b) is carried out in tetrahydrofuran. 4.The method according to claim 1, wherein the protecting group istetrahyd ropyranyl.
 5. The method according to claim 1 or 2, wherein theprotecting group is benzyl.
 6. The method according claim 1 or 2,wherein X in the alkylating reagent in step a) or step b) is I or Br. 7.The method according claim 1, wherein X in the alkylating reagent instep c) is I, Br, or Cl.
 8. The method according to claim 1 or 2,wherein the alkylation in step c) is carried out in by use of i)potassium carbonate and absolute ethanol, or ii) sodium hydride andtetrahydrofuran.
 9. The method according to claim 1 or 2, wherein thereduction of compound (V) obtained in step c) is carried out by lithiumaluminum hydride.
 10. The method according to any of the foregoingclaims where the compound (Ia) or (Ib) is the Z-isomer.
 11. A method forthe preparation of a compound of formula (Ia)

(Ia) comprising: wherein a compound of formula (II)

is alkylated with an alkylating reagent of the formulaX—(CH₂)₂—O—(CH₂)₂—O-Pr, where X is Cl, Br, I, mesyloxy or tosyloxy, andPr is a protecting group, to give a compound of formula (III)

which is subjected to removal of the protecting group Pr to give thecompound of formula (Ia), wherein the compound (Ia) is the Z-isomer. 12.The method of claim 11, wherein X is I.
 13. The method of claim 11,wherein Pr is tetrahydropyranyl or benzyl.
 14. The method of claim 13,wherein Pr is 2-tetrahydropyranyl.
 15. The method of claim 11, whereinthe protecting group Pr is removed using acid.
 16. The method of claim13, wherein Pr is benzyl and is removed using zinc and acetyl chloride.17. A method for the preparation of a compound of formula (Ib)

(Ib) comprising: wherein a compound of formula (II)

is alkylated with an alkylating reagent of the formula X—(CH₂)₂—O-Pr,where X is Cl, Br, I, mesyloxy or tosyloxy, and Pr is a protectinggroup, to give a compound of formula (IV)

which is subjected to removal of the protecting group Pr to give thecompound of formula (Ib), wherein the compound (Ib) is the Z-isomer. 18.The method of claim 17, wherein X is I.
 19. The method of claim 17,wherein Pr is tetrahydropyranyl or benzyl.
 20. The method of claim 17,wherein Pr is 2-tetrahydropyranyl.
 21. The method of claim 20, whereinthe protecting group Pr is removed using acid.
 22. The method of claim19, wherein Pr is benzyl and is removed using zinc and acetyl chloride.23. A method for the preparation of a compound of formula (Ib):

(Ib) comprising: wherein a compound of formula (II)

is alkylated with an alkylating reagent of the formula X—CH₂—COOR,wherein X is Cl, Br, I, mesyloxy or tosyloxy, and R is an alkyl, to givea compound of formula (V)

and the ester group of V is reduced to give the compound of formula(Ib), wherein the compound (Ib) is the Z-isomer.
 24. The method of claim23, wherein X is Br.
 25. The method of claim 24, wherein R is a C₁₋₄alkyl.
 26. The method of claim 25, wherein R is ethyl.
 27. The method ofclaim 23, wherein said ester is reduced using lithium aluminum hydride.